Abstract
As an essential regulator of DNA damage, ataxia-telangiectasia mutated (ATM) gene has been widely studied in oncology. However, the independent effects of ATM missense variants and protein-truncating variants (PTVs) on neoplasms have not been heavily studied. Whole-exome sequencing data and the clinical health records of 394,694 UK Biobank European participants were used in this analysis. We mined genetic associations from gene-level and variant-level phenome-wide association studies, and conducted a variant-level conditional association study to test whether the effects of ATM missense variants on neoplasms were independent of ATM PTV carrier status. The gene-level PTV collapsing analysis was consistent with established ATM PTV literature showing that the aggregated impact of 286 ATM PTVs significantly (p < 2 × 10-9 ) associated with 31 malignant neoplasm phenotypes. Of 773 distinct protein-coding variants in ATM, three individual missense variants significantly (p < 2 × 10-9 ) associated with nine phenotypes. Remarkably, although the nine phenotypes were tumor-related, none overlapped the established ATM PTV-linked malignancies. A subsequent conditional analysis identified that the missense signals were acting independently of the known clinically relevant ATM PTVs.